MRCP PART 1 & 2

NOTES FROM PASSMEDICINE, PASTEST, Notes & notes

By ABDULLAH TANVIR

THYROID

● On a simple level hypothalamus secrets TRH which stimulates anterior pituitary to secrete
TSH
● This then acts on thyroid gland increasing production of T4 & T3

CAUSES

Hypothyroidism Thyrotoxicosis

Hashimoto's thyroiditis Graves' disease

● Most common cause in developed world ● Most common cause of
● Associated with type 1 DM, Addison's or thyrotoxicosis
pernicious anaemia
● May cause transient thyrotoxicosis in acute phase Toxic multinodular goitre
● 5-10 times more common in women ● autonomously functioning
thyroid nodules that secrete
Subacute thyroiditis (de Quervain's) excess thyroid hormones
● Associated with a painful goitre & raised ESR
Subacute thyroiditis (de
Postpartum thyroiditis Quervain's)

Riedel thyroiditis Postpartum thyroiditis

● Fibrous tissue replacing normal thyroid
parenchyma Drugs
● Causes a painless goitre ● Amiodarone
● Heparin (Can cause transient
Drugs rise in serum thyroid
● Lithium hormones
● Amiodarone

Iodine deficiency
● Most common cause of hypothyroidism in
developing world

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 CLINICAL FEATURES

Feature Hypothyroidism Thyrotoxicosis

General Weight gain Weight loss

Lethargy Manic, restlessness
Cold intolerance Heat intolerance

Cardiac - Palpitations, may even provoke

arrhythmias e.g. atrial fibrillation

Reversible cardiomyopathy
High output HF

Skin Dry (anhidrosis), cold, yellowish skin Increased sweating

Non-pitting oedema Pretibial myxoedema: Erythematous,
Dry, coarse scalp hair, loss of lateral oedematous lesions above lateral
aspect of eyebrows malleoli
Thyroid acropachy : Clubbing

Gastrointestinal Constipation Diarrhoea

Gynaecological Menorrhagia Oligomenorrhea

Neurological Decreased deep tendon reflexes Anxiety

Carpal tunnel syndrome Tremor

Investigation
● Principle investigation : thyroid function tests / TFTs
○ These primarily look at serum TSH and T4 levels
○ T3 can be measured but is only useful clinically in a small number of cases
○ T3 levels should be performed where tests show normal T4 with suppressed TSH
● TSH levels are more sensitive than T4 levels for monitoring patients with existing thyroid
problems and are often used to guide treatment

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 INTERPRETATION OF THYROID FUNCTION TESTS

Diagnosis TSH Free T4 Notes

Primary Thyrotoxicosis Low High In T3 thyrotoxicosis free T4 :

(e.g. Graves' disease) Normal

Secondary hyperthyroidism High High

Primary hypothyroidism High Low

(primary atrophic
hypothyroidism)

Secondary hypothyroidism Low Low Replacement steroid therapy is

required prior to thyroxine

Sick euthyroid syndrome / Low / Low Common in hospital inpatients. T3

non-thyroidal illness Normal is particularly low in these patients

Subclinical hypothyroidism High Normal

Poor compliance with High Normal

thyroxine

A number of thyroid autoantibodies can be tested for (remember the majority of thyroid disorders
are autoimmune). The 3 main types are:
● Anti-thyroid peroxidase (anti-TPO) antibodies
● TSH receptor antibodies
● Thyroglobulin antibodies

Other tests include:

● Nuclear scintigraphy
○ Low patchy uptake : Toxic multinodular goitre
○ Diffuse, homogenous, increased uptake : Graves’ disease
○ Low / No uptake : Viral, Postpartum, iodine / drug induced thyrotoxicosis

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 HYPERTHYROIDISM

Causes
● Graves' disease (Most common)
● Toxic nodular goitre
● Acute phase of subacute (de Quervain's) thyroiditis
● Acute phase of postpartum thyroiditis
● Acute phase of Hashimoto's thyroiditis (later results in hypothyroidism)
● Amiodarone therapy
● Contrast
○ Rare, more commonly occurs in elderly patients with pre-existing thyroid disease
(e.g. multinodular goitre, Graves')
○ Patients with existing thyrotoxicosis should not receive iodinated contrast medium
○ Administration of iodinated contrast results in a large iodine load to the thyroid →
hyperthyroidism developing over 2-12 weeks

Investigation
● TSH down, T4 and T3 up
● TSH antibodies
● If antibody test is negative : Radionuclide thyroid uptake scan can help determine the cause

Management
● Propranolol : To control thyrotoxic symptoms such as tremor
● Carbimazole : Blocks thyroid peroxidase from coupling & iodinating the tyrosine residues
on thyroglobulin → reducing thyroid hormone production
○ Agranulocytosis is an important adverse effect to be aware of
● Radioiodine treatment

● Sore throat without neutropenia : Continue carbimazole

● Neutropenia : Discontinue carbimazole & substituted by propylthiouracil till neutrophil
count has recovered & plan for radioactive iodine

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 GRAVE'S DISEASE

● Most common cause of thyrotoxicosis. It is typically seen in women aged 30-50 years.

Features
● Typical features of thyrotoxicosis
● Features seen in Graves' but not in other causes of thyrotoxicosis
● Eye signs (30% of patients) : Exophthalmos, Ophthalmoplegia
● Pretibial myxoedema
● Thyroid acropachy, a triad of: Digital clubbing, Soft tissue swelling of hands & feet
and Periosteal new bone formation

Investigation
● Autoantibodies
○ TSH receptor stimulating antibodies (90%)
○ Anti-thyroid peroxidase antibodies (75%)
● Thyroid scintigraphy
○ Diffuse, homogenous, increased uptake of radioactive iodine

MANAGEMENT

Treatment options
● Antithyroid drugs (ATDs, for example carbimazole)
● Radioiodine treatment
● Surgery

Initial treatment to control symptoms

● Propranolol is used to help block the adrenergic effects
● Carbimazole should be considered in primary care if patients symptoms are not controlled
with propranolol

ATD therapy
● Carbimazole is started at 40mg and reduced gradually to maintain euthyroidism
● Typically continued for 12-18 months
● Major complication of carbimazole therapy : Agranulocytosis

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 ● An alternative regime is termed 'block-and-replace'
○ carbimazole is started at 40mg
○ thyroxine is added when the patient is euthyroid
○ treatment typically lasts for 6-9 months
○ patients following an ATD titration regime have been shown to suffer fewer
side-effects than those on a block-and-replace regime

Radioiodine treatment
● Often used in patients who relapse following ATD therapy or are resistant to primary ATD
treatment
● Contraindications
○ Pregnancy (should be avoided for 4-6 months following treatment)
○ Age < 16 years
○ Thyroid eye disease is a relative contraindication, as it may worsen the condition
● Majority of patient will require thyroxine supplementation after 5 years

TOXIC MULTINODULAR GOITRE

Investigation
● Nuclear scintigraphy reveals patchy uptake.

Treatment
● Treatment of choice : Radioiodine therapy

Subacute (De Quervain's) thyroiditis

● Occur following viral infection and typically presents with hyperthyroidism.

There are typically 4 phases;

● phase 1 (lasts 3-6 weeks): hyperthyroidism, painful goitre, raised ESR
● phase 2 (1-3 weeks): euthyroid
● phase 3 (weeks - months): hypothyroidism
● phase 4: thyroid structure and function goes back to normal

Investigations
● Thyroid scintigraphy: globally reduced uptake of iodine-131

Management

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 ● Usually self-limiting - most patients do not require treatment
● Thyroid pain may respond to aspirin or other NSAIDs
● In more severe cases steroids are used, particularly if hypothyroidism develops

SUBCLINICAL HYPERTHYROIDISM

● Serum free T4 & T3 : Normal, TSH : below normal range (usually < 0.1 mu/l)

Causes
● Multinodular goitre, particularly in elderly females
● Excessive thyroxine may give a similar biochemical picture

Effects
● Atrial fibrillation
● Osteoporosis
● Increase the likelihood of dementia

Management
● TSH levels often revert to normal - levels must be persistently low to warrant intervention
● A reasonable treatment option is a therapeutic trial of low-dose antithyroid agents for
approximately 6 months in an effort to induce a remission

THYROID STORM

● Rare but life-threatening complication of thyrotoxicosis

● Typically seen in patients with established thyrotoxicosis & rarely seen as presenting
feature
● Iatrogenic thyroxine excess does not usually result in thyroid storm

Precipitating events:
● Thyroid or non-thyroidal surgery
● Trauma
● Infection
● Acute iodine load e.g. CT contrast media

Clinical features include:

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 ● Fever > 38.5ºC, tachycardia
● Confusion & agitation, nausea & vomiting
● Hypertension, heart failure
● Abnormal liver function test - jaundice may be seen clinically

Management
● Symptomatic treatment e.g. paracetamol
● Treatment of underlying precipitating event
● 1st line : IV beta-blockers (typically IV propranolol)
● Antithyroid drugs : Propylthiouracil is preferred due to rapid onset of action
● Lugol's iodine
● Dexamethasone - e.g. 4mg IV qds - blocks the conversion of T4 to T3
● In acute thyrotoxicosis, stop aspirin as it can worsen the storm by displacing T4 from TBG

HYPOTHYROIDISM

Hypothyroidism may be classified as follows:

● Primary hypothyroidism : Problem with the thyroid gland itself
● Secondary hypothyroidism : Usually due to a disorder with pituitary gland
● Congenital hypothyroidism : Due to a problem with thyroid dysgenesis or thyroid
dyshormonogenesis

Management
● Target TSH : 0.5-2.5 mU/l
● Following a change in thyroxine dose : TFTs should be checked after 8-12 weeks
● Women with established hypothyroidism who become pregnant : Increase 'by at least
25-50 micrograms levothyroxine
● No evidence to support combination therapy with levothyroxine & liothyronine
● Iron, calcium carbonate : Reduce absorption of levothyroxine, give at least 4 hours apart

Side-effects of thyroxine therapy

● Hyperthyroidism: due to over treatment
● Reduced bone mineral density
● Worsening of angina
● Atrial fibrillation

RIEDEL’S THYROIDITIS

● Rare cause of hypothyroidism characterised by dense fibrous tissue replacing normal

thyroid parenchyma

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 ● It is usually seen in middle-aged women
● A hard, fixed, painless goitre is noted
● It is associated with retroperitoneal fibrosis

SUBCLINICAL HYPOTHYROIDISM

● TSH raised but T3, T4 normal

● No obvious symptoms

Significance
● risk of progressing to overt hypothyroidism is 2-5% per year (higher in men)
● risk increased by presence of thyroid autoantibodies

Management
● Not all patients require treatment
● Consider offering levothyroxine if TSH > 10 mU/L on 2 separate occasions 3 months apart
● TSH is between 5.5 - 10mU/L : Consider offering a 6-month trial of levothyroxine if < 65
years & Symptoms of hypothyroidism
● In older people (especially those > 80 years) follow a 'watch and wait' strategy
● If asymptomatic people : observe & repeat thyroid function in 6 months

MYXOEDEMA COMA

● Myxoedema coma typically presents with confusion and hypothermia.

Management
● IV thyroid replacement
● IV fluid
● IV corticosteroids (until the possibility of coexisting adrenal insufficiency has been excluded)
● Electrolyte imbalance correction
● Sometimes rewarming

THYROID EYE DISEASE

● Thyroid eye disease affects between 25-50% of patients with Graves' disease.
● Autoimmune response against an autoantigen, possibly TSH receptor → Retro-orbital
inflammation > Inflammation results in glycosaminoglycan & collagen deposition in muscles

Features
● Patient may be eu-, hypo- or hyperthyroid at the time of presentation

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 ● Exophthalmos
● Conjunctival oedema
● Optic disc swelling
● Ophthalmoplegia
● Inability to close the eyelids may lead to sore, dry eyes. If severe and untreated patients
can be at risk of exposure keratopathy

Prevention
● Smoking is the most important modifiable risk factor for development of thyroid eye disease
● Radioiodine treatment may increase inflammatory symptoms seen in thyroid eye disease
● Prednisolone may help reduce the risk

Management
● Topical lubricants may be needed to help prevent corneal inflammation caused by exposure
● Rx of choice for moderately severe active Graves' ophthalmopathy : IV methylprednisolone
● Radiotherapy
● Surgery

Following symptoms/signs should indicate need for urgent review by an ophthalmologist

● unexplained deterioration in vision
● awareness of change in intensity or quality of colour vision in one or both eyes
● history of eye suddenly 'popping out' (globe subluxation)
● obvious corneal opacity
● cornea still visible when the eyelids are closed
● disc swelling

THYROID CANCER

● Features of hyperthyroidism or hypothyroidism are not commonly seen in patients with

thyroid malignancies as they rarely secrete thyroid hormones

Type Notes

Papillary ● Usually contain a mixture of papillary and colloid filled follicles

carcinoma ● Histologically tumour has papillary projections and pale empty nuclei
● Seldom encapsulated
70% ● Lymph node metastasis predominates. Haematogenous metastasis rare
● Excellent prognosis

Follicular ● Usually present as a solitary thyroid nodule

adenoma ● Malignancy can only be excluded on formal histological assessment

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Follicular ● Macroscopically encapsulated, microscopically capsular invasion is seen.
carcinoma Without this finding the lesion is a follicular adenoma.
● Vascular invasion predominates
20% ● Multifocal disease raree

Medullary ● C cells derived from neural crest & not thyroid tissue
carcinoma ● Serum calcitonin levels often raised
● Part of MEN 2
5% ● Both lymphatic & haematogenous metastasis are recognised
● Nodal disease is associated with a very poor prognosis.
● Investigation
○ Confirmatory : Pentagastrin stimulation test

Anaplastic ● Most common in elderly females

carcinoma ● Local invasion is a common feature
● Can cause pressure symptoms
1% Treatment
● Not responsive to treatment
● Resection where possible
● Palliation may be achieved through isthmusectomy & radiotherapy
● Chemotherapy is ineffective.

Lymphoma ● Associated with Hashimoto's thyroiditis

Rare

Workup for thyroid nodules is as follows:

● Check TSH
○ TSH suppressed → Thyroid uptake scan
■ Cold / Iso nodule → FNAC
■ Hot nodule → No FNAC required
○ TSH normal/elevated → Thyroid USS → Suspicious features → FNA cytology

Management of papillary & follicular carcinoma

● Size >1cm or any signs of metastatic : Total thyroidectomy
● > 4cm OR 1-4 cm with extrathyroid disease OR histology high risk : Postoperative
radioiodine ablation
● Monitoring : Yearly thyroglobulin levels
● A non-palpable thyroid mass < 1 cm in size found incidentally on imaging without worrying
features does not need biopsy

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 PREGNANCY : THYROID

● Raised total T3 & T4 but normal fT3 & fT4 suggest high concentrations of TBG which can
be seen during pregnancy
● Pregnant woman with a history of Grave’s disease should have TSH binding antibody
titres measured even if euthyroid as the antibodies can cross placental barrier

PREGNANCY : THYROTOXICOSIS

● Untreated thyrotoxicosis increases risk of foetal loss, maternal heart failure & premature
labour
● Graves' disease is the most common cause of thyrotoxicosis in pregnancy
● Activation of TSH receptor by HCG may also occur - transient gestational hyperthyroidism
● HCG levels will fall in second & third trimester

Management
● First trimester : Propylthiouracil
○ Carbimazole may be associated with an increased risk of congenital abnormalities
● At the beginning of 2nd trimester : Switch to carbimazole
● Maternal free thyroxine levels should be kept in the upper third of normal reference range
to avoid foetal hypothyroidism
● Thyrotropin receptor stimulating antibodies should be checked at 30-36 weeks gestation -
helps to determine the risk of neonatal thyroid problems
● Radioiodine therapy is contraindicated
● Block-and-replace regimes should not be used in pregnancy

PREGNANCY : HYPOTHYROIDISM

Key points
● Thyroxine is safe during pregnancy
● Serum TSH measured in each trimester & 6-8 weeks postpartum
● Women require an increased dose of thyroxine during pregnancy
○ By up to 50% as early as 4-6 weeks of pregnancy
● Breastfeeding is safe whilst on thyroxine

POSTPARTUM THYROIDITIS

Three stages
● Thyrotoxicosis

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 ● Hypothyroidism
● Normal thyroid function (but high recurrence rate in future pregnancies)

Investigation
● Thyroid peroxidase antibodies are found in 90% of patients

Management
● Thyrotoxic phase
○ Propranolol is typically used for symptom control
○ Not usually treated with antithyroid drugs as the thyroid is not overactive.
● Hypothyroid phase
○ Usually treated with thyroxine

RADIOIODINE THERAPY

● Nearly all the iodine ingested is taken up by the thyroid gland. It is an essential element for
the formation of T3 and T4
● Radioiodine therapy involves using radioactive iodine (I-131 isotope)
● The radiation can destroy thyroid gland & any other thyroid cells (including cancer cells)
that take up iodine, with little effect on the rest of the body.

Indications
● Differentiated thyroid cancer
● Toxic multinodular goitre
● Graves disease refractory to medical management
● Radiation exposure: Potassium iodine has been used to help individuals exposed to
radiation by reducing the harmful accumulation of radioactive substances in the thyroid

Method
● TSH is required for iodine uptake by thyroid cells. In order to effectively treat with
radioactive iodine, TSH levels have to be increased to stimulate any thyroid cells into taking
up the radioactive iodine. This is done by either making patients hypothyroid after stopping
thyroid hormone or by treating with recombinant human TSH.
● A capsule of radioactive iodine is ingested. A clear perspex tube is used to transport the
capsule into the patient's mouth to avoid skin contact.
● Once the capsule has been ingested the patient can leave the isotopes unit.

Advice post procedure

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 ● After radioactive iodine, patients should be advised to keep babies, children under five,
pregnant women and pets at arm’s length for two to three weeks
● Not to become pregnant for at least six months after radioactive iodine treatment
● Male patients are advised not to cause a pregnancy for six months after radioactive iodine

Contraindications
● Pregnancy
● Breastfeeding
● Active thyroid eye disease (unless providing steroid cover)
● Radioiodine therapy should be avoided until 8 weeks following CT contrast administration

Complications
● Thyroid pain
● Hypothyroidism
● Flare of Graves' eye disease

Follow up
● Monitoring of patients thyroid function (hypothyroidism is the commonest complication of
radioiodine therapy)
● For thyroid cancers, monitoring of thyroglobulin
● If thyroglobulin concentrations are initially elevated in a person diagnosed with thyroid
cancer, then it is likely that thyroglobulin can be used as a tumour marker

PARATHYROID

PRIMARY HYPERPARATHYROIDISM

● Most common cause of hypercalcaemia in outpatients

● In 85% of cases a parathyroid adenoma is responsible.
● Associations : Hypertension, Neoplasia: MEN I and II

Causes of primary hyperparathyroidism

● 85%: solitary adenoma
● 10%: hyperplasia
● 4%: multiple adenoma
● 1%: carcinoma

Features
● Around 80% of patients are asymptomatic
● Polydipsia, polyuria
● Depression, anorexia, nausea, constipation, peptic ulceration

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 ● Pancreatitis
● Bone pain/fracture, renal stones
● Hypertension

Investigations
● Raised Ca, low phosphate
● PTH : Raised or normal (inappropriately, given raised calcium)
● Technetium-MIBI subtraction scan
● x-ray findings : Pepperpot skull, osteitis fibrosa cystica

Treatment
● Definitive management : Total parathyroidectomy
● Patients not suitable for surgery may be treated with cinacalcet, a calcimimetic
● Conservative management may be offered if
○ Ca < 0.25 mmol/L above the upper limit of normal AND
○ Patient > 50 years AND
○ No evidence of end-organ damage

Indications for parathyroidectomy

● Symptomatic hyperparathyroidism
● Asymptomatic hyperparathyroidism with any of the following:
○ 24-hour urinary calcium > 400 mg
○ Serum calcium > 1 mg/dL above upper limit of normal
○ Creatinine clearance > 30% below normal for patient's age
○ Bone density > 2.5 standard deviations for below peak (i.e., T-score of -2.5)
○ People age < 50

Monitoring
● Serum Ca & Renal function
● Consider a DEXA scan at diagnosis & every 2 to 3 years' in people with primary
hyperparathyroidism who have not had parathyroidectomy.

HYPOPARATHYROIDISM

The main symptoms of hypoparathyroidism are secondary to hypocalcemia:

● Tetany: muscle twitching, cramping and spasm, perioral paraesthesia
● Trousseau's sign: carpal spasm if the brachial artery occluded by inflating the blood
pressure cuff and maintaining pressure above systolic
● Chvostek's sign: tapping over parotid causes facial muscles to twitch
● if chronic: depression, cataracts
● ECG: prolonged QT interval

PSEUDOHYPOPARATHYROIDISM

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 ● Caused by target cell insensitivity to PTH due to a mutation in a G-protein
● In type I pseudohypoparathyroidism : Complete receptor defect whereas in type II the cell
receptor is intact
● Autosomal dominant fashion

Features
● Short fourth & fifth metacarpals, short stature
● Learning difficulties
● Obesity, round face

Investigation
● ↑ PTH, ↓ calcium, ↑ phosphate
● Diagnosis : By measuring urinary cAMP and phosphate levels following an infusion of PTH.
○ Hypoparathyroidism : Increase in both cAMP and phosphate levels.
○ Pseudohypoparathyroidism I : neither cAMP nor phosphate levels are increased
○ Pseudohypoparathyroidism II : only cAMP rises
● Treatment : Calcium & vitamin D supplementation

Abnormalities
● Pseudohypoparathyroidism Type 1a : Both (biochemistry + clinical features)
● pseudohypoparathyroidism Type 1b : Only biochemistry + NO clinical features
● Pseudopseudohypoparathyroidism : Only clinical features + normal biochemistry

Hungry bone syndrome

● Can occur after parathyroidectomy if the hyperparathyroidism has been long-standing

● High preoperative levels of PTH provide a constant stimulus for osteoclast activity creating
the hypercalcaemic state by demineralizing the bones. This process can result in x-ray
changes very similar to metastatic lytic lesions if left untreated
● Upon removal of the parathyroid adenoma hormone levels fall rapidly (they have a very
short half-life) & the osteoclast activity is subsequently diminished and the bones rapidly
begin re-mineralisation - 'hungry bone syndrome'
● This process can be uncomfortable and also result in systemic hypocalcaemia.

HYPERCALCEMIA

Causes
● Primary hyperparathyroidism : Commonest cause in non-hospitalised patients
● Malignancy : Commonest cause in hospitalised patients. Due to

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 ○ PTHrP from the tumour e.g. squamous cell lung cancer
○ Bone metastases
○ Myeloma : Due primarily to increased osteoclastic bone resorption caused by local
cytokines (e.g. IL-1, tumour necrosis factor) released by myeloma cells
● Sarcoidosis
○ Other causes of granulomas may lead to hypercalcaemia e.g. TB & histoplasmosis
● Vitamin D intoxication
● Acromegaly
● Thyrotoxicosis
● Milk-alkali syndrome
● Drugs: Thiazides, calcium-containing antacids
● Dehydration
● Addison's disease
● Paget's disease of bone
○ Usually normal but hypercalcaemia may occur with prolonged immobilisation

Investigation
● Measuring PTH levels is the key investigation for patients with hypercalcaemia

Management
● Initial management of hypercalcaemia : Rehydration with normal saline, typically 3-4 L / day
● Following rehydration bisphosphonates may be used
○ They typically take 2-3 days to work with maximal effect being seen at 7 days
● 2nd line
○ Calcitonin (if poor response to bisphosphonate),
○ Calcimimetics (if parathyroid ca, renal failure or primary hyperparathyroidism),
○ Parathyroidectomy (if primary hyperparathyroidism) or
○ Glucocorticoids (e.g. if lymphoma, granulomatous disease or vit D overdose)
Familial benign hypocalciuric hypercalcaemia

● A rare autosomal dominant disorder characterised by asymptomatic hypercalcaemia.

● PTH level is often not suppressed, as would be expected in all non-hyperparathyroidism
related cases of hypercalcaemia
● Due to a defect in the calcium-sensing receptor & a decreased sensitivity to increases in
extracellular calcium.

HYPOCALCEMIA

Causes
● Vitamin D deficiency (osteomalacia)
● Chronic kidney disease
● Hypoparathyroidism (e.g. post thyroid/parathyroid surgery)

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 ● Pseudohypoparathyroidism (target cells insensitive to PTH)
● Magnesium deficiency (due to end organ PTH resistance)
● Rhabdomyolysis (Initial stages)
● Massive blood transfusion
● Acute pancreatitis
● Contamination of blood samples with EDTA may also give falsely low calcium levels.

Management
● Severe hypocalcemia (e.g. carpopedal spasm, tetany, seizures or prolonged QT interval) :
IV calcium replacement
○ Preferred method : IV calcium gluconate 10 ml of 10% solution over 10 min
○ IV calcium chloride is more likely to cause local irritation
○ ECG monitoring is recommended
● Further management depends on the underlying cause

ADRENAL GLAND DISORDERS

PHEOCHROMOCYTOMA

● Catecholamine secreting tumour. About 10% are familial

● May be associated with MEN type II, neurofibromatosis & von Hippel-Lindau syndrome

Basics
● bilateral in 10%, malignant in 10%, extra-adrenal in 10% (most common site = organ of
Zuckerkandl, adjacent to the bifurcation of aorta)

Features are typically episodic

● hypertension (around 90% of cases, may be sustained), palpitations
● headaches, sweating, anxiety

Investigation
● 24 hr urinary collection of metanephrines (sensitivity 97%*)
● 24 hr urinary collection of catecholamines (sensitivity 86%)

Management
● Surgery is the definitive management

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 ● Patient must first however be stabilised with medical management : alpha-blocker (e.g.
phenoxybenzamine), given before a beta-blocker (e.g. propranolol)

CUSHING'S SYNDROME

Causes
● Exogenous / iatrogenic (e.g. glucocorticoid therapy) : Most common
● ACTH dependent causes
● Cushing's disease (80%) : Pituitary tumour secreting ACTH producing adrenal
hyperplasia
● Ectopic ACTH production (5-10%): e.g. SCLC (Most common cause)
● ACTH independent causes
○ Iatrogenic : Steroids
○ Adrenal adenoma (5-10%)
○ Adrenal carcinoma (rare)
○ Micronodular adrenal dysplasia (very rare)

Clinical features
● A hypokalemic metabolic alkalosis may be seen, along with impaired glucose tolerance.
● Ectopic ACTH secretion is characteristically associated with very low potassium levels

Pseudo-Cushing's
● Mimics Cushing's
● Often due to alcohol excess or severe depression
● Features
○ Causes false positive dexamethasone suppression test or 24 hr urinary free cortisol
○ Normal or mildly raised serum cortisol, a raised urine free cortisol
● Some Cushing's symptoms such as striae, easy bruising & proximal myopathy are not
usually seen in pseudo-Cushing's
● A hallmark of true Cushing's syndrome is lack of diurnal variation in serum cortisol.
● However in pseudo-Cushing's diurnal variation is normally maintained

INVESTIGATION

Tests to confirm Cushing's syndrome

● Overnight (low-dose) dexamethasone suppression test
○ Most sensitive test and is now used first-line to test for Cushing's syndrome
○ Patients of Cushing's syndrome do not have their morning cortisol spike suppressed
● 24 hr urinary free cortisol : Two measurements are required
● Bedtime salivary cortisol : Two measurements are required

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To differentiate between Cushing & pseudo cushing
● An insulin stress test is used to differentiate between true Cushing's and pseudo-Cushing's
○ Pseudo Cushing : A rise in cortisol levels >170 nmol following an insulin stress test

Localisation tests
● First-line localisation : 9am & midnight plasma ACTH (and cortisol) levels
○ If ACTH is suppressed : Non-ACTH dependent cause is likely such as an adrenal
adenoma
● High-dose dexamethasone suppression test

Cortisol ACTH Interpretation

Suppressed Suppressed Cushing's disease (i.e. pituitary adenoma → ACTH

secretion)

Not suppressed Not suppressed Ectopic ACTH syndrome

Not suppressed Suppressed Cushing's syndrome due to other causes (e.g. adrenal
adenomas)

Other tests
● CRH stimulation
○ If pituitary source then cortisol rises
○ If ectopic / adrenal then no change in cortisol
● Petrosal sinus sampling of ACTH may be needed to differentiate between pituitary &
ectopic ACTH secretion.

ADRENAL INSUFFICIENCY

Features
● Lethargy, weakness,weight loss, 'salt-craving'
● Anorexia, Nausea & vomiting, Hypotension
● Hyperpigmentation (especially palmar creases)*, vitiligo
○ Primary Addison's is associated with hyperpigmentation whereas secondary adrenal
insufficiency is not
● Loss of pubic hair in women
● Crisis: collapse, shock, pyrexia
● Associated metabolic abnormalities : Hypoglycaemia, Hyponatraemia, Hyperkalaemia,
Metabolic acidosis

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Causes
● Primary causes
○ Autoimmune destruction of adrenal glands : Commonest cause
○ Tuberculosis, HIV, Meningococcal septicaemia (Waterhouse-Friderichsen syndrome)
○ Metastases (e.g. bronchial carcinoma)
○ Antiphospholipid syndrome
● Secondary causes
○ Pituitary disorders (e.g. tumours, irradiation, infiltration)
○ Exogenous glucocorticoid therapy

Investigation
● Definitive : ACTH stimulation test (short Synacthen test).
● If an ACTH stimulation test is not readily available (e.g. in primary care) then sending a 9
am serum cortisol can be useful:
○ > 500 nmol/l : Addison's very unlikely
○ < 100 nmol/l : Definitely abnormal
○ 100 - 500 nmol/l : Should prompt a ACTH stimulation test to be performed
● Borderline short synacthen test : Do Long Synacthen test
● To distinguish primary adrenal failure from secondary adrenal failure
○ ACTH
○ Long Synacthen test : Significant rise in cortisol indicates secondary adrenal failure

Management
● Usually given both glucocorticoid & mineralocorticoid replacement therapy.
● Hydrocortisone: usually given in 2 or 3 divided doses
● Patients typically require 20-30 mg per day, with the majority given in the first half of the day
● A cortisol curve can be used to assess how appropriate dosing of glucocorticoid steroids
in Addison’s disease patients is

Management of intercurrent illness

● Glucocorticoid dose should be doubled, with the fludrocortisone dose staying the same
● A person with Addisons’ who vomits should take IM hydrocortisone until vomiting stops
● If patient is unwell with systemic involvement : Admission for IV fluids & IV
hydrocortisone

Other conditions
● For strenuous exercise (such as a marathon) : Double the normal dose of glucocorticoid
and mineralocorticoid, as well as sufficient fluids.

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 ● For gentle short duration exercise (such as walking) : Does not generally need to make a
dose adjustment.
● For sports or activities with a risk of injury (such as skiing) the person should ensure that
a teammate is trained in administration of emergency hydrocortisone if needed.

ADDISONIAN CRISIS

Causes
● Sepsis or surgery causing an acute exacerbation of chronic insufficiency (Addison's,
Hypopituitarism)
● Adrenal haemorrhage eg Waterhouse-Friderichsen syndrome (fulminant meningococcemia)
● Steroid withdrawal

Management
● Hydrocortisone 100 mg im or iv
○ Continue hydrocortisone 6 hourly until the patient is stable
● 1 litre normal saline infused over 30-60 mins or with dextrose if hypoglycemic
● No fludrocortisone is required because high cortisol exerts weak mineralocorticoid action
● Oral replacement may begin after 24 hours and be reduced to maintenance over 3-4 days

Waterhouse-Friderichsen syndrome

● Waterhouse-Friderichsen syndrome describes adrenal gland failure secondary to a

previous adrenal haemorrhage that was caused by severe bacterial infection.

Causes
● Neisseria meningitidis: most common cause
● Haemophilus influenzae
● Pseudomonas aeruginosa
● Escherichia coli
● Streptococcus pneumoniae

The features are those of hypoadrenalism, i.e.:

● lethargy, weakness, anorexia, nausea & vomiting, weight loss
● hyperpigmentation (especially palmar creases), vitiligo, loss of pubic hair in women

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 ● crisis: collapse, shock, pyrexia

PRIMARY HYPERALDOSTERONISM

Causes
● Bilateral idiopathic adrenal hyperplasia : Cause of around 60-70% of cases
● Adrenal adenoma: 20-30% of cases
● Unilateral hyperplasia
● Familial hyperaldosteronism
● Adrenal carcinoma

Features
● Hypertension : Increasingly recognised but still underdiagnosed cause of hypertension
● Hypokalaemia : muscle weakness
○ A classical feature in exams but seen in only 10-40% of patients, and is more
common with adrenal adenomas
● Metabolic alkalosis

Investigations
● Certain patients should be screened for primary hyperaldosteronism, e.g.
○ Hypertension with hypokalemia
○ Treatment-resistant hypertension
● First-line in suspected primary hyperaldosteronism : Plasma aldosterone/renin ratio
○ High aldosterone levels alongside low renin levels
● To confirm the location of aldosterone excess : HRCT abdomen & adrenal vein sampling
○ If CT is normal / Most reliable : Adrenal venous sampling (AVS)

Management
● Adrenal adenoma : Surgery (laparoscopic adrenalectomy)
● Bilateral adrenocortical hyperplasia : Aldosterone antagonist e.g. spironolactone

From passmedicine
● Aldosterone increases on prolonged standing = Adrenal hyperplasia
● Aldosterone falls / similar on prolonged standing = Conn's adenoma

CONGENITAL ADRENAL HYPERPLASIA

Overview
● Group of autosomal recessive disorders

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 ● Affect adrenal steroid biosynthesis
● Low cortisol synthesis > (+) secretion of ACTH > Increased adrenal androgens > may
virilize a female infant

Cause
● 21-hydroxylase deficiency (90%)
○ Virilisation of female genitalia
○ Precocious puberty in males
○ 60-70% of patients have a salt-losing crisis at 1-3 wks of age
○ Increased 17-hydroxyprogesterone (17 OHP)
● 11-beta hydroxylase deficiency (5%)
○ Virilisation of female genitalia
○ Precocious puberty in males
○ Hypertension, Hypokalaemia
● 17-hydroxylase deficiency (very rare)
○ Non-virilisation in females
○ Inter-sex in boys
○ Hypertension
○ Increased 11-deoxycortisol & 11-deoxycorticosterone

Diagnosis
● ACTH stimulation / short synacthen test is used to confirm the diagnosis
● Elevated levels of serum of 17-hydroxyprogesterone (17 OHP). Very high level is diagnostic

Mnemonic : if there's a 1 in front- HTN. If there's a 1 at back- virilisation

● 21- hydroxylase: 1 at back only so: no HTN, only virilisation
● 11-hydroxylase: 1 in both front and back- so both HTN and virilisation
● 17- only 1 in front- so only HTN,no virilisation

ANDROGEN INSENSITIVITY SYNDROME

● X-linked recessive condition due to end-organ resistance to testosterone

● Genotypically male children (46XY) to have a female phenotype
● Complete androgen insensitivity syndrome : new term for testicular feminisation syndrome

Features
● Primary amenorrhoea
● Little or no axillary and pubic hair
● Undescended testes causing groin swellings
● Breast development may occur as a result of the conversion of testosterone to oestradiol

Diagnosis

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 ● Buccal smear or chromosomal analysis to reveal 46 XY genotype
● After puberty, testosterone concentrations are in high-normal to slightly elevated reference
range for postpubertal boys

Management
● Counselling - raise the child as female
● Bilateral orchidectomy (increased risk of testicular cancer due to undescended testes)
● Oestrogen therapy

KLINEFELTER'S SYNDROME

● Karyotype 47, XXY

Features
● often taller than average
● lack of secondary sexual characteristics
● Small, firm testes, infertile
● gynaecomastia - increased incidence of breast cancer
● elevated gonadotropin levels

Diagnosis : Chromosomal analysis

Kallmann's syndrome

● A recognised cause of delayed puberty secondary to hypogonadotropic hypogonadism.

● Usually inherited as an X-linked recessive trait
● Caused by failure of GnRH-secreting neurons to migrate to hypothalamus.
● Clue : Lack of smell (anosmia) in a boy with delayed puberty.

Features
● Delayed puberty
● Hypogonadism, cryptorchidism
● Anosmia
● Patients are typically of normal or above-average height
● Cleft lip /palate and visual/ hearing defects are also seen in some patients

Investigation
● Sex hormone levels are low
● LH, FSH levels are inappropriately low/normal

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Management
● Testosterone supplementation
● Gonadotropin supplementation may result in sperm production if fertility is desired
● HCG and FSH then IVF

5-α reductase deficiency

● 46 XY
● Autosomal recessive condition.
● Results in inability of males to convert testosterone to dihydrotestosterone (DHT)

Features
● Ambiguous genitalia in the newborn period
● Hypospadias is common.
● Virilization at puberty

DISORDERS OF SEX HORMONES

Disorder LH Testosterone

Primary hypogonadism High Low

(Klinefelter's syndrome)

Hypogonadotrophic Low Low

hypogonadism (Kallman's
syndrome)

Androgen insensitivity High Normal/high

syndrome

Testosterone-secreting Low High

tumour

POLYCYSTIC OVARIAN SYNDROME

Features
● Subfertility & infertility
● Menstrual disturbances: oligomenorrhea & amenorrhoea
● Hirsutism, acne (due to hyperandrogenism)
● Obesity
● Acanthosis nigricans (due to insulin resistance)

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Investigations
● Pelvic ultrasound : Multiple cysts on ovaries
● Raised LH : FSH ratio is a 'classical' feature but is no longer thought to be useful in
diagnosis
○ Prolactin may be normal or mildly elevated
○ Testosterone may be normal or mildly elevated - however, if markedly raised
consider other causes
○ SHBG is normal to low in women with PCOS
● Check for impaired glucose tolerance

Management
● General
○ Weight reduction if appropriate
○ if a women requires contraception then a COC pill may help regulate her cycle &
induce a monthly bleed
● Hirsutism and acne
○ COC pill may be used help manage hirsutism
■ Possible options : Third generation COC which has fewer androgenic effects
or co-cyprindiol which has an anti-androgen action
■ Both of these types may carry an increased risk of venous thromboembolism
○ If doesn't respond to COC : Topical eflornithine may be tried
○ Spironolactone, flutamide and finasteride may be used under specialist supervision
● Infertility
○ Weight reduction if appropriate
○ Clomifene was the most effective treatment
○ Metformin is also used, either combined with clomifene or alone, particularly in
patients who are obese
○ Gonadotropins

PITUITARY GLAND

HYPOPITUITARISM

● Describes inadequate production of one or more of hormones secreted by pituitary gland.

Causes

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 ● Compression of pituitary gland by non-secretory pituitary macroadenoma (most common)
● Pituitary apoplexy
● Sheehan's syndrome : Postpartum pituitary necrosis secondary to a postpartum
haemorrhage
● Hypothalamic tumours e.g. craniopharyngioma
● Trauma
● Iatrogenic irradiation / Surgery
● Infiltrative e.g. hemochromatosis, sarcoidosis

Clinical features depend on which hormones are deficient:

● Low ACTH : Tiredness, postural hypotension
● Low FSH/LH : Amenorrhoea, infertility, loss of libido
● Low TSH : Feeling cold, constipation
● Low GH : if occurs during childhood then short stature
● Low prolactin : Problems with lactation
● Features suggestive of the underlying causes
○ Pituitary macroadenoma → bitemporal hemianopia
○ Pituitary apoplexy → sudden, severe headache

Investigations
● For growth hormone deficiency
○ Insulin tolerance test
■ Contraindications : IHD, Seizures & Severe hypopituitarism
○ Patients with IHD or seizures : Arginine-GHRH stimulation test
● Imaging

Management
● Treatment of any underlying cause (e.g. surgical removal of pituitary macroadenoma)
● Replacement of deficient hormones

PITUITARY ADENOMA

● A pituitary adenoma is a benign tumour of pituitary gland

● Most common type : Prolactinomas
● Non-secreting adenomas are the next most common, then GH-secreting & then ACTH-
secreting adenomas.

Classification
● Microadenoma is < 1 cm : Prolactin levels usually 1500 - 4000.
● Macroadenoma is ≥1 cm : Prolactin levels > 6000.
● Non functioning pituitary adenomas (NFPA) : Prolactin is modest (approx 2000 - 3000)
○ Can cause hyperprolactinemia due to pituitary stalk compression

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 ○ Do not present until > 1cm in size
● Features of a macroadenoma (e.g. bitemporal hemianopia, headache etc) : Prolactin level
can be very useful for distinguishing what the pathology is.
○ Very high in prolactin macroadenoma & only modestly elevated in NFPA

Presentation
● Excess of a hormone
○ e.g. Cushing’s disease due to excess ACTH, acromegaly due to excess GH or
amenorrhea & galactorrhea due to excess prolactin)
● Depletion of a hormone(s)
○ Due to compression of normal functioning pituitary gland
○ Non-functioning tumours, therefore, present with generalised hypopituitarism
● Headaches
● Compression of optic chiasm causing a bitemporal hemianopia
● Can be an incidental finding on neuroimaging

Investigation
● Pituitary blood profile (including GH, prolactin, ACTH, FSH, LSH and TFTs)
● Formal visual field testing
● MRI brain with contrast

Management
● First line treatment for all pituitary tumours : Surgery (e.g. transsphenoidal transnasal
hypophysectomy)
● Exception : Hormonal therapy for prolactinomas
○ First line : Cabergoline
○ In pregnancy : Bromocriptine

Microprolactinoma
● Monitoring : Yearly MRI

PROLACTIN & GALACTORRHEA

● Prolactin is secreted by anterior pituitary gland with release being controlled by a wide
variety of physiological factors
● Dopamine acts as primary prolactin releasing inhibitory factor & hence dopamine agonists
such as bromocriptine may be used to control galactorrhoea

Features of excess prolactin

● Men: impotence, loss of libido, galactorrhoea
● Women: amenorrhoea, galactorrhoea

Causes of raised prolactin

● Prolactinoma

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 ● Pregnancy, Oestrogens
● Physiological : stress, exercise, sleep
● Acromegaly: 1/3 of patients
● Polycystic ovarian syndrome
● Primary hypothyroidism (due to TRH stimulating prolactin release)

Drug causes of raised prolactin

● Metoclopramide, domperidone
● Phenothiazines, haloperidol
● Very rare: SSRIs, opioids

ACROMEGALY

● Excess growth hormone secondary to a pituitary adenoma in over 95% of cases

● Minority of cases are caused by ectopic GHRH or GH production by tumours e.g.
pancreatic

Features
● Coarse facial appearance, spade-like hands, increase in shoe size
● Large tongue, prognathism / Overbite, interdental spaces
● Excessive sweating and oily skin: caused by sweat gland hypertrophy
● Features of pituitary tumour : Hypopituitarism, headaches, bitemporal hemianopia
● Raised prolactin in 1/3 of cases → galactorrhoea
● 6% of patients have MEN-1
● Carpal tunnel syndrome : Positive Tinel's sign

Complications
● Hypertension, Diabetes (>10%)
● Cardiomyopathy
● Colorectal cancer

Investigation
● 1st line / Initial screening test / Monitoring : Serum IGF-1 levels
● Confirmatory : OGTT with serial GH measurements

Management
● Trans-sphenoidal surgery is the first-line treatment
● If patients are not suitable for surgery, or have residual symptoms after surgery :
Octreotide
● External irradiation is sometimes used for older patients or following failed surgical/medical
treatment
● Pegvisomant
○ GH receptor antagonist - prevents dimerization of the GH receptor
○ Once daily s/c administration

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 ○ Very effective - decreases IGF-1 levels in 90% of patients to normal
○ Doesn't reduce tumour volume therefore surgery still needed if mass effect
● Should be offered regular colonoscopy screening starting at the age of 40 years

MULTIPLE ENDOCRINE NEOPLASIA

● MEN is inherited as an autosomal dominant disorder.

MEN type I MEN type IIa MEN type IIb

Parathyroid (95%): Parathyroid (60%) Pheochromocytoma

hyperparathyroidism due to Pheochromocytoma Medullary thyroid cancer
parathyroid hyperplasia Medullary thyroid cancer (70%) Marfanoid body habitus
Pituitary (70%) Neuromas
Pancreas (50%): e.g. insulinoma,
gastrinoma
Also: adrenal & thyroid

MEN1 gene RET oncogene RET oncogene

Most common presentation :

hypercalcaemia

Serum PTH Serum Calcitonin

Autoimmune polyendocrinopathy syndrome

APS type 1
● Referred to as Multiple Endocrine Deficiency Autoimmune Candidiasis (MEDAC)
● Autosomal recessive disorder caused by mutation of AIRE1 gene on chromosome 21
● Features of APS type 1 (2 out of 3 needed)
○ Chronic mucocutaneous candidiasis (typically first feature as young child)
○ Addison's disease
○ primary hypoparathyroidism
APS type 2 has a polygenic inheritance & linked to HLA DR3/DR4. Patients have Addison's
disease plus either:
● type 1 diabetes mellitus
● autoimmune thyroid disease

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 Vitiligo can occur in both types

WATER DEPRIVATION TEST

Starting plasma Final urine osm. Urine osm.

osm. post-DDAVP

Normal Normal > 600 > 600

Psychogenic Low > 400 > 400

polydipsia

Cranial DI High < 300 > 600

Nephrogenic DI High < 300 < 300

OBESITY

MANAGEMENT

The management of obesity consists of a step-wise approach:

● Conservative : diet, exercise
● Medical : orlistat, liraglutide
○ Orlistat should only be used when > 3 months use of dietary & lifestyle measures
has failed.
● Surgical

Orlistat
● A pancreatic lipase inhibitor
● Adverse effects : faecal urgency / incontinence & flatulence.
● Indications
○ BMI of 28 kg/m^2 or more with associated risk factors, or
○ BMI of 30 kg/m^2 or more
○ Continued weight loss e.g. 5% at 3 months
○ Orlistat is normally used for < 1 year

Liraglutide
● GLP-1 mimetic

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 ● A once daily subcutaneous injection
● Criteria for use (see link for full criteria):
○ BMI of at least 35 kg/m²
○ Prediabetic hyperglycaemia (e.g. HbA1c 42 - 47 mmol/mol)

Surgery is recommended if:

● Failure of non-surgical measures (no clinically beneficial weight loss over 6 months)
2 2
● BMI of 40 kg/m or more, or a BMI of 35–40 kg/m & other significant disease that could
be improved if they lost weight.
2
● BMI greater than 50 kg/m .
● Ppatient commits to long-term follow-up which needs to be done under the supervision of
a specialist obesity team.

URINARY INCONTINENCE

Classification
● Overactive bladder (OAB) / urge incontinence
○ Due to detrusor overactivity
○ Urge to urinate is quickly followed by uncontrollable leakage ranging from a few
drops to complete bladder emptying
● Stress incontinence : leaking small amounts when coughing or laughing
● Mixed incontinence : both urge and stress
● Overflow incontinence: due to bladder outlet obstruction, e.g. due to prostate enlargement
● Functional incontinence
○ comorbid physical conditions impair the patient’s ability to get to a bathroom in time
○ causes include dementia, sedating medication and injury/illness resulting in
decreased ambulation

Initial investigation
● Urge incontinence : urodynamic studies
● Bladder diaries should be completed for a minimum of 3 days
● Vaginal examination to exclude pelvic organ prolapse & ability to initiate voluntary
contraction of pelvic floor muscles ('Kegel' exercises)
● Urine dipstick and culture

Management

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Urge incontinence is predominant:
● Bladder retraining (lasts for a minimum of 6 weeks, the idea is to gradually increase
intervals between voiding)
● Bladder stabilising drugs : Antimuscarinics are first-line
○ Oxybutynin (immediate release), tolterodine (immediate release) or darifenacin (once
daily preparation)
○ Immediate release oxybutynin should, however, be avoided in 'frail older women'
○ Mirabegron (a beta-3 agonist) : Concern about anticholinergic side-effects in frail
elderly patients

If stress incontinence is predominant:

● Pelvic floor muscle training
○ At least 8 contractions performed 3 times per day for a minimum of 3 months
● Surgical procedures: e.g. retropubic mid-urethral tape procedures
● Duloxetine may be offered to women if they decline surgical procedures

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